5-Bromophthalide Chemical Properties

Melting point:

162-166 °C(lit.)

Boiling point:

377.7±42.0 °C(Predicted)

Density 

1.742±0.06 g/cm3(Predicted)

storage temp. 

Inert atmosphere,Room Temperature

solubility 

Soluble in acetone.

form 

Crystalline Powder

color 

Beige to light yellow

InChI

InChI=1S/C8H5BrO2/c9-6-1-2-7-5(3-6)4-11-8(7)10/h1-3H,4H2

InChIKey

IUSPXLCLQIZFHL-UHFFFAOYSA-N

SMILES

C1(=O)C2=C(C=C(Br)C=C2)CO1

CAS DataBase Reference

64169-34-2(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

37/39-26

WGK Germany 

2

RTECS 

EJ9940000

HS Code 

29329990

MSDS

• Language:English Provider:ACROS
• Language:English Provider:SigmaAldrich

5-Bromophthalide Usage And Synthesis

Chemical Properties

5-Bromophthalide is white to Pale Yellow Crystalline Solid

Uses

5-Bromophthalide is a useful synthetic intermediate

Uses

5-Bromophthalide is an important organic intermediate. It can be used in agrochemical, pharmaceutical and dyestuff field. It is a key intermediate of citalopram.

Synthesis

The general procedure for the synthesis of 5-bromophthalide from 5-aminophthalide was as follows: first, 5-nitrophthalimide (8) was prepared by nitration of phthalimide (7), using 200 g of phthalimide (7) in a mixture of HNO3 and H2SO4 acids at 0 °C to give 146 g of the product (8) in 56% yield. Subsequently, 8 was reduced to amine 9 by catalytic hydrogenation, using 5% Pd/C as catalyst, in EtOAc solvent in 97% yield. This step encountered the bottleneck of high solvent usage in large-scale operation. The improved method used the catalytic reduction reaction of zinc powder and copper(II) sulfate in 6 M NaOH aqueous solution to prepare aminophthalide 10 directly from 8 in one step in 100% yield, which effectively solved the bottleneck problem. Aminophthalide 10 was converted to 5-bromophthalide 11 in 76% yield by the Sandmeyer reaction in the presence of NaNO2 and 4 M HBr at 0 °C, followed by the addition of CuBr. A single batch yielded 36 g of 11. Next, 11 was reduced by diisobutylaluminum hydride (DIBAL) in toluene at -42 °C to give bromolactone 12 in 77% yield . Finally, 12 was reacted with boron trifluoride ether compounds in methanol to prepare bromoacetal 6 in 96% yield. The whole synthetic route was efficient and only the last two steps (e and f) required purification of the product by chromatography.

References

[1] Patent: US2011/77394, 2011, A1. Location in patent: Page/Page column 15
[2] Patent: CN108383833, 2018, A. Location in patent: Paragraph 0013
[3] Journal of the Chemical Society, 1931, p. 867,869
[4] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1195 - 1204
[5] European Journal of Medicinal Chemistry, 2010, vol. 45, # 5, p. 1941 - 1946

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